Urea substituted benzothiazoles

ABSTRACT

The present invention relates to compounds of formula I  
                 
 
     wherein  
     R 1  and R 2  are described herein, and their pharmaceutically acceptable salts thereof for the treatment of diseases, related to the A 2A  receptor.

FIELD OF THE INVENTION

[0001] The present invention relates to compounds of the general formula

[0002] wherein R¹, R² and n are described hereinbelow. These ligands(compounds) have a good affinity to the A_(2A)-receptor and a highselectivity to the A₁- and A₃ receptors. These compounds are useful,inter alia, in treatment of Alzheimer's disease, depression, Parkinson'sdisease and ADHD.

BACKGROUND OF THE INVENTION

[0003] Adenosine modulates a wide range of physiological functions byinteracting with specific cell surface receptors. The potential ofadenosine receptors as drug targets was first reviewed in 1982.Adenosine is related both structurally and metabolically to thebioactive nucleotides adenosine triphosphate (ATP), adenosinediphosphate (ADP), adenosine monophosphate (AMP) and cyclic adenosinemonophosphate (cAMP); to the biochemical methylating agentS-adenosyl-L-methione (SAM); and structurally to the coenzymes NAD, FADand coenzym A; and to RNA. Together adenosine and these relatedcompounds are important in the regulation of many aspects of cellularmetabolism and in the modulation of different central nervous systemactivities.

[0004] The receptors for adenosine have been classified as A₁, A_(2A),A_(2B) and A₃ receptors, belonging to the family of G protein-coupledreceptors. Activation of adenosine receptors by adenosine initiatessignal transduction mechanism. These mechanisms are dependent on thereceptor associated G protein. Each of the adenosine receptor subtypeshas been classically characterized by the adenylate cydase effectorsystem, which utilises cAMP as a second messenger. The A₁ and A₃receptors, coupled with G_(i) proteins inhibit adenylate cyclase,leading to a decrease in cellular cAMP levels, while A_(2A) and A_(2B)receptors couple to G_(s) proteins and activate adenylate cyclase,leading to an increase in cellular cAMP levels. It is known that the A₁receptor system include the activation of phospholipase C and modulationof both potassium and calcium ion channels. The A₃ subtype, in additionto its association with adenylate cyclase, also stimulates phospholipaseC and so activates calcium ion channels.

[0005] The A₁ receptor (326-328 amino acids) was cloned from variousspecies (canine, human, rat, dog, chick, bovine, guinea-pig) with 90-95%sequence identify among the mammalian species. The A_(2A) receptor(409-412 amino acids) was cloned from canine, rat, human, guinea pig andmouse. The A_(2B) receptor (332 amino acids) was cloned from human andmouse with 45% homology of human A_(2B) with human A₁ and A_(2A)receptors. The A₃ receptor (317-320 amino acids) was cloned from human,rat, dog, rabbit and sheep.

[0006] The A₁ and A_(2A) receptor subtypes are proposed to playcomplementary roles in adenosine's regulation of the energy supply.Adenosine, which is a metabolic product of ATP, diffuses from the celland acts locally to activate adenosine receptors to decrease the oxygendemand (A₁) or increase the oxygen supply (A_(2A)) and so reinstate thebalance of energy supply: demand within the tissue. The action of bothsubtypes is to increase the amount of available oxygen to tissue and toprotect cells against damage caused by a short term imbalance of oxygen.One of the important functions of endogenous adenosine is preventingdamage during traumas such as hypoxia, ischaemia, hypotension andseizure activity.

[0007] Furthermore, it is known that the binding of the adenosinereceptor agonist to mast cells expressing the rat A₃ receptor resultedin increased inositol triphosphate and intracellular calciumconcentrations, which potentiated antigen induced secretion ofinflammatory mediators. Therefore, the A₃ receptor plays a role inmediating asthmatic attacks and other allergic responses.

[0008] Adenosine is a neuromodulator, able to modulate many aspects ofphysiological brain function. Endogenous adenosine, a central linkbetween energy metabolism and neuronal activity, varies according tobehavioral state and (patho)physiological conditions. Under conditionsof increased demand and decreased availability of energy (such ashypoxia, hypoglycemia, and/or excessive neuronal activity), adenosineprovides a powerful protective feedback mechanism. Interacting withadenosine receptors represents a promising target for therapeuticintervention in a number of neurological and psychiatric diseases suchas epilepsy, sleep, movement disorders (Parkinson or Huntington'sdisease), Alzheimer's disease, depression, schizophrenia, or addiction.An increase in neurotransmitter release follows traumas such as hypoxia,ischaemia and seizures. These neurotransmitters are ultimatelyresponsible for neural degeneration and neural death, which causes braindamage or death of the individual. The adenosine A₁ agonists which mimicthe central inhibitory effects of adenosine may therefore be useful asneuroprotective agents. Adenosine has been proposed as an endogenousanticonvulsant agent, inhibiting glutamate release from excitory neuronsand inhibiting neuronal firing. Adenosine agonists therefore may be usedas antiepileptic agents.

[0009] Adenosine antagonists stimulate the activity of the CNS and haveproven to be effective as cognition enhancers. Selective A_(2a)antagonists have therapeutic potential in the treatment of various formsof dementia, for example in Alzheimer's disease, and ofneurodegenerative disorders, e.g. stroke. Adenosine A_(2a) receptorantagonists modulate the activity of striatal GABAergic neurons andregulate smooth and well-coordinated movements, thus offering apotential therapy for Parkinsonian symptoms. Adenosine is alsoimplicated in a number of physiological processes involved in sedation,hypnosis, schizophrenia, anxiety, pain, respiration, depression, anddrug addiction (amphetamine, cocaine, opioids, ethanol, nicotine,cannabinoids). Drugs acting at adenosine receptors therefore havetherapeutic potential as sedatives, muscle relaxants, antipsychotics,anxiolytics, analgesics, respiratory stimulants, antidepressants, and totreat drug abuse. They may also be used in the treatment of ADHD(attention deficit hyper-activity disorder).

[0010] An important role for adenosine in the cardiovascular system isas a cardioprotective agent. Levels of endogenous adenosine increase inresponse to ischaemia and hypoxia, and protect cardiac tissue during andafter trauma (preconditioning). By acting at the A₁ receptor, adenosineA₁ agonists may protect against the injury caused by myocardial ischemiaand reperfusion. The modulating influence of A₂a receptors on adrenergicfunction may have implications for a variety of disorders such ascoronary artery disease and heart failure. A_(2a) antagonists may be oftherapeutic benefit in situations in which an enhanced antiadrenergicresponse is desirable, such as during acute myocardial ischemia.Selective antagonists at A_(2a) receptors may also enhance theeffectiveness of adenosine in terminating supraventricula arrhytmias.

[0011] Adenosine modulates many aspects of renal function, includingrenin release, glomerular filtration rate and renal blood flow.Compounds which antagonise the renal affects of adenosine have potentialas renal protective agents. Furthermore, adenosine A₃ and/or A_(2B)antagonists may be useful in the treatment of asthma and other allergicresponses or and in the treatment of diabetes mellitus and obesity.

[0012] Numerous documents describe the current knowledge on adenosinereceptors. These include Bioorganic & Medicinal Chemistry, 6, (1998),619-641; Bioorganic & Medicinal Chemistry, 6, (1998), 707-719; J. Med.Chem., (1998), 41, 2835-2845; J. Med. Chem., (1998), 41, 3186-3201; J.Med. Chem., (1998), 41, 2126-2133; J. Med. Chem., (1999), 42, 706-721;J. Med. Chem., (1996), 39, 1164-1171; Arch. Pharm. Med. Chem., 332,39-41, (1999); Am. J. Physiol., 276, H1113-1116, (1999) and NaunynSchmied, Arch. Pharmacol. 362, 375-381, (2000).

SUMMARY OF THE INVENTION

[0013] An aspect of the present invention is directed to a compound offormula I

[0014] wherein

[0015] R¹ is selected from the group consisting of

[0016] cyclopentyl,

[0017] cyclopentyl substituted by CF₃,

[0018] cyclopentyl substituted by lower alkyl,

[0019] cyclopentyl substituted by —(CH₂)_(n)OH,

[0020] cyclopentyl substituted by —(CH₂)_(n)-O-lower alkyl,

[0021] cyclohexyl,

[0022] cyclohexyl substituted by CF₃,

[0023] cyclohexyl substituted by lower alkyl,

[0024] cyclohexyl substituted by —(CH₂)_(n)OH,

[0025] cyclohexyl substituted by —(CH₂)_(n)-O-lower alkyl,

[0026] 1-bicyclo[2.2.1]hept-2-yl,

[0027] 1-(7-oxa-bicyclo[2.2.1]hept-2-yl,

[0028] 1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-exo-yl,

[0029] 1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-endo-yl, and

[0030] 1-adamantan-1-yl; and

[0031] R² is lower alkyl; or

[0032] R¹ and R² form together with the N-atom the group8-oxa-3-aza-bicyclo[3.2.1]octane; and

[0033] n is 0 or 1;

[0034] or a pharmaceutically acceptable salt thereof.

[0035] Other embodiments of this invention are directed to methods ofmanufacturing compounds of formula I, a pharmaceutical compositioncontaining a compound of formula I, and a pharmaceutically acceptablesalt thereof, as well as a method of controlling or prevention ofillnesses based on the modulation of the adenosine system, such asAlzheimer's disease, Parkinson's disease, Huntington's disease,neuroprotection, schizophrenia, anxiety, pain, respiration deficits,depression, drug addiction, such as amphetamine, cocaine, opioids,ethanol, nicotine, cannabinoids, or against asthma, allergic responses,hypoxia, ischaemia, seizure and substance abuse comprising administeringto a patient a therapeutically effective amount of a compound of formulaI or a pharmaceutically acceptable salt thereof.

[0036] Furthermore, compounds of the present invention are useful assedatives, muscle relaxants, antipsychotics, antiepileptics,anticonvulsants and cardiaprotective agents for disorders such ascoronary artery disease and heart failure. Preferred indications inaccordance with the present invention are those that depend on theA_(2A) receptor antagonistic activity and which include disorders of thecentral nervous system, for example the treatment or prevention ofAlzheimer's disease, certain depressive disorders, drug addiction,neuroprotection and Parkinson's disease as well as ADHD.

DETAILED DESCRIPTION OF THE INVENTION

[0037] As used herein, the term “lower alkyl” denotes a saturatedstraight- or branched-chain alkyl group containing from 1 to 6 carbonatoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl,2-butyl, t-butyl and the like.

[0038] The term “pharmaceutically acceptable acid addition salts”embraces salts with inorganic and organic acids, such as hydrochloricacid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formicacid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaricacid, methane-sulfonic acid, p-toluenesulfonic acid and the like.

[0039] The term “therapeutically effective amount” refers to an amountof at least one compound of formula I, or a pharmaceutically acceptablesalt thereof, tha modulates adenosine.

[0040] The present invention is related to a compound of formula I

[0041] wherein

[0042] R¹ is selected from the group consisting of

[0043] cyclopentyl,

[0044] cyclopentyl substituted by CF₃,

[0045] cyclopentyl substituted by lower alkyl,

[0046] cyclopentyl substituted by —(CH₂)_(n)OH,

[0047] cyclopentyl substituted by —(CH₂)_(n)-O-lower alkyl,

[0048] cyclohexyl,

[0049] cyclohexyl substituted by CF₃,

[0050] cyclohexyl substituted by lower alkyl,

[0051] cyclohexyl substituted by —(CH₂)_(n)OH,

[0052] cyclohexyl substituted by —(CH₂)_(n)-O-lower alkyl,

[0053] 1-bicyclo[2.2.1]hept-2-yl,

[0054] 1-(7-oxa-bicyclo[2.2. 1]hept-2-yl,

[0055] 1-(5-exo-hydroxy-bicyclo [2.2.1]hept-2-exo-yl,

[0056] 1-(5-exo-hydroxy-bicyclo [2.2.1]hept-2-endo-yl, and

[0057] 1-adamantan-1-yl; and

[0058] R² is lower alkyl; or

[0059] R¹ and R² form together with the N-atom the group8-oxa-3-aza-bicyclo[3.2.1]octane; and

[0060] n is 0 or 1;

[0061] or a pharmaceutically acceptable salt thereof.

[0062] In another embodiment, the present invention is related to acompound of formula I

[0063] wherein

[0064] R¹ is selected from the group consisting of

[0065] cyclopentyl,

[0066] cyclopentyl substituted by CF₃,

[0067] cyclopentyl substituted by lower alkyl,

[0068] cyclopentyl substituted by —(CH₂)_(n)OH,

[0069] cyclopentyl substituted by —(CH₂)_(n)-O-lower alkyl,

[0070] cyclohexyl,

[0071] cyclohexyl substituted by CF₃,

[0072] cyclohexyl substituted by lower alkyl,

[0073] cyclohexyl substituted by —(CH₂)_(n)OH,

[0074] cyclohexyl substituted by —(CH₂)_(n)-O-lower alkyl,

[0075] 1-bicyclo[2.2.1]hept-2-yl,

[0076] 1-(7-oxa-bicyclo[2.2.1]hept-2-yl,

[0077] 1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-exo-yl,

[0078] 1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-endo-yl, and

[0079] 1-adamantan-1-yl;

[0080] R² is lower alkyl; and

[0081] n is 0 or 1;

[0082] or a pharmaceutically acceptable salt thereof.

[0083] In another embodiment, this invention is related to a compound offormula I

[0084] wherein, R¹ and R² form together with the N-atom the group8-oxa-3-aza-bicyclo[3.2.1]octane;

[0085] or a pharmaceutically acceptable salt thereof.

[0086] In a preferred embodiment, the compound of formula I is where R¹is cyclopentyl.

[0087] In another preferred embodiment, the compound of formula I iswhere R¹ is cyclopentyl substituted by CF₃.

[0088] In another preferred embodiment, the compound of formula I iswhere R¹ is cyclopentyl substituted by lower alkyl.

[0089] In another preferred embodiment, the compound of formula I iswhere R¹ is cyclopentyl substituted by —(CH₂)_(n)OH, and n is 0 or 1.

[0090] In another preferred embodiment, the compound of formula I iswhere R¹ is cyclopentyl substituted by —(CH₂)_(n)-O-lower alkyl, and nis 0 or 1.

[0091] In another preferred embodiment, the compound of formula I iswhere R¹ is cyclohexyl.

[0092] In another preferred embodiment, the compound of formula I whereR¹ is cyclohexyl substituted by CF₃.

[0093] In another preferred embodiment, the compound of formula I iswhere R¹ iscyclohexyl substituted by lower alkyl.

[0094] In another preferred embodiment, the compound of formula I iswhere R¹ is cyclohexyl substituted by —(CH₂)_(n)OH, and n is 0 or 1.

[0095] In another preferred embodiment, the compound of formula I iswhere R¹ is cyclohexyl substituted by —(CH₂)_(n)-O-lower alkyl, and n is0 and 1.

[0096] In another preferred embodiment, the compound of formula I iswhere R¹ is 1-bicyclo[2.2.1]hept-2-yl.

[0097] In another preferred embodiment, the compound of formula I iswhere R¹ is 1-(7-oxa-bicyclo[2.2.1]hept-2-yl.

[0098] In another preferred embodiment, the compound of formula I iswhere R¹ is 1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-exo-yl.

[0099] In another preferred embodiment, the compound of formula I iswhere R¹ is 1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-endo-yl.

[0100] In another preferred embodiment, the compound of formula I iswhere R¹ is 1-adamantan-1 -yl.

[0101] In another preferred embodiment, the compound of formula I iswhere R¹ and R² form together with the N-atom the group8-oxa-3-aza-bicyclo[3.2.1]octane.

[0102] Preferred compounds are those, wherein R¹ is cyclopentyl,cyclopentyl substituted by CF₃, cyclopentyl substituted by lower alkyl,cyclopentyl substituted by —(CH₂)_(n)OH, cyclopentyl substituted by—(CH₂)_(n)-O-lower alkyl, cyclohexyl, cyclohexyl substituted by CF₃,cyclohexyl substituted by lower alkyl, cyclohexyl substituted by—(CH₂)_(n)OH, cyclohexyl substituted by —(CH₂)_(n)-O-lower alkyl, forexample the following compounds:

[0103]3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-1-(4-trifluoromethyl-cyclohexyl)-urea,

[0104](trans)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-1-(4-methyl-cyclohexylurea,

[0105](trans)-1-(4-hydroxymethyl-cyclohexyl)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea,

[0106](trans)-1-(4-methoxymethyl-cyclohexyl)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-ureaor

[0107] (rac),(cis)-1-(3-hydroxymethyl-cyclopentyl)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea.

[0108] Further preferred are those compounds, wherein R¹ is

[0109] 1-bicyclo[2.2.1]hept-2-yl, 1-(7-oxa-bicyclo[2.2.1]hept-2-yl,1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-exo-yl,1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-endo-yl or

[0110] 1-adamantan-1-yl, for example the following compounds:

[0111]1-(endo)-(rac)-bicyclo[2.2.1]hept-2-yl-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea,

[0112](exo)-(+)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-1-(7-oxa-bicyclo[2.2.1]hept-2-yl)-urea,

[0113](exo)-(−)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-1-(7-oxa-bicyclo[2.2.1]hept-2-yl)-urea,

[0114](rac)-(endo)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-1-(7-oxa-bicyclo[2.2.1]hept-2-yl)-urea,

[0115](rac)-1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-exo-yl)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea,

[0116](rac)-1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-endo-yl)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-ureaor

[0117]1-adamantan-1-yl-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea.

[0118] An example for compounds, wherein R¹ and R² form together withthe N-atom the group 8-oxa-3-aza-bicyclo[3.2.1]octane is8-oxa-3-aza-bicyclo [3.2.1]octane-3-carboxy acid(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide.

[0119] The present compounds of formula I and their pharmaceuticallyacceptable salts can be prepared by methods known in the art, forexample, by processes described below, which process comprises reactinga compound of formula

[0120] with a compound of formula

[0121] to produce a compound of formula

[0122] wherein R¹ is selected from the group consisting of

[0123] cyclopentyl,

[0124] cyclopentyl substituted by CF₃,

[0125] cyclopentyl substituted by lower alkyl,

[0126] cyclopentyl substituted by —(CH₂)_(n)OH,

[0127] cyclopentyl substituted by —(CH₂)_(n)-O-lower alkyl,

[0128] cyclohexyl,

[0129] cyclohexyl substituted by CF₃,

[0130] cyclohexyl substituted by lower alkyl,

[0131] cyclohexyl substituted by —(CH₂)_(n)OH,

[0132] cyclohexyl substituted by —(CH₂)_(n)-O-lower alkyl,

[0133] 1-bicyclo[2.2.1]hept-2-yl,

[0134] 1-(7-oxa-bicyclo[2.2.1]hept-2-yl,

[0135] 1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-exo-yl,

[0136] 1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-endo-yl, and

[0137] 1-adamantan-1-yl; and

[0138] R² is lower alkyl; and

[0139] n is 0 or 1.

[0140] The present compounds of formula I and their pharmaceuticallyacceptable salts can also be prepared by methods known in the art, forexample, by processes described below, which process comprises reactinga compound of formula

[0141] with a compound of formula

[0142] to produce a compound of formula

[0143] wherein R¹ is selected from the group consisting of

[0144] cyclopentyl,

[0145] cyclopentyl substituted by CF₃,

[0146] cyclopentyl substituted by lower alkyl,

[0147] cyclopentyl substituted by —(CH₂)_(n)OH,

[0148] cyclopentyl substituted by —(CH₂)_(n)-O-lower alkyl,

[0149] cyclohexyl,

[0150] cyclohexyl substituted by CF₃,

[0151] cyclohexyl substituted by lower alkyl,

[0152] cyclohexyl substituted by —(CH₂)_(n)OH,

[0153] cyclohexyl substituted by —(CH₂)_(n)-O-lower alkyl,

[0154] 1-bicyclo[2.2.1]hept-2-yl,

[0155] 1-(7-oxa-bicyclo[2.2.1]hept-2-yl,

[0156] 1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-exo-yl,

[0157] 1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-endo-yl, and

[0158] 1-adamantan-1-yl; and

[0159] R² is lower alkyl;

[0160] n is 0 or 1;

[0161] L is a leaving group selected from the group consisting ofhalogen, —O-phenyl and O-lower alkyl.

[0162] If desired, the resulting compound in the above two processes canfurther be converted into its pharmaceutically acceptable salt.

[0163] In Examples 1-13 and in the following schemes 1 and 2 thepreparation of compounds of formula I are described in more detail.

[0164] The starting materials are known compounds or may be preparedaccording to methods known in the art.

[0165] Preparation of Compounds of Formula I

[0166] The intermediate7-(morpholin-4-yl)-4-methoxy-benzothiazol-2-ylamine (II) may be preparedaccording to methods disclosed in WO01/97786. The preparation ofcompounds of formula (I) using the intermediate of formula (II) is alsodescribed in WO01/97786.

[0167] One method of preparation-of compounds of formula (I) inaccordance with the following scheme 1 is as follows: To a solution ofthe compound of formula (II) in dichloromethane is subsequently added abase, e.g. pyridine or diisopropyl-ethylamine and a compound of formula(III), and the resulting solution is stirred for about 45 min at ambienttemperature. Saturated aqueous sodium hydrogen carbonate is added, theorganic phase is separated and dried.

[0168] Another method of preparation of compounds of formula (I) is asfollows: To a solution of the compound of formula (IV), which can beprepared according to methods well known to the art and which isdescribed in WO01/97786, in an inert solvent, e.g. dichloromethane, issubsequently added a base, e.g. pyridine or diisopropyl-ethylamine and acompound of formula (V), and the resulting solution is stirred for about45 min at 45° C. After cooling to ambient temperature, saturated aqueoussodium hydrogen carbonate is added, the organic phase is separated anddried.

[0169] Isolation and Purification of the Compounds

[0170] Isolation and purification of the compounds and intermediatesdescribed herein can be effected, if desired, by any suitable separationor purification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography,thick-layer chromatography, preparative low or high-pressure liquidchromatography or a combination of these procedures. Specificillustrations of suitable separation and isolation procedures can be hadby reference to the preparations and examples herein below. However,other equivalent separation or isolation procedures could, of course,also be used.

[0171] Salts of Compounds of Formula I

[0172] The compounds of formula I maybe basic, for example in caseswhere the residue R contains a basic group such as an aliphatic oraromatic amine moiety. In such cases the compounds of formula I may beconverted to a corresponding salt.

[0173] The conversion is accomplished by treatment with at least astoichiometric amount of an appropriate acid, such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, and organic acids such as acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic add,maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. Typically, the freebase is dissolved in an inert organic solvent such as diethyl ether,ethyl acetate, chloroform, ethanol or methanol and the like, and theacid added in a similar solvent. The temperature is maintained between0° C. and 50° C. The resulting salt precipitates spontaneously or may bebrought out of solution with a less polar solvent.

[0174] The salts of the basic compounds of formula I may be converted tothe corresponding free bases by treatment with at least a stoichiometricequivalent of a suitable base such as sodium or potassium hydroxide,potassium carbonate, sodium bicarbonate, ammonia, and the like.

[0175] The compounds of formula I and their pharmaceutically acceptablesalts possess valuable pharmacological properties. Specifically, it hasbeen found that the compounds of the present invention are adenosinereceptor ligands and possess a high affinity towards the adenosineA_(2A) receptor.

[0176] The compounds were investigated in accordance with the test givenhereinafter.

Human Adenosine A_(2A) Receptor

[0177] The human adenosine A_(2A) receptor was recombinantly expressedin Chinese hamster ovary (CHO) cells using the semliki forest virusexpression system. Cells were harvested, washed twice by centrifugation,homogenized and again washed by centrifugation. The final washedmembrane pellet was suspended in a Tris (50 mM) buffer containing 120 mMNaCl, 5 mM KCl, 2 mM CaCl₂ and 10 mM MgCl₂ (pH 7.4) (buffer A). The[³H]-SCH-58261 (Dionisotti et al., 1997, Br J Pharmacol 121, 353; 1nM)binding assay was carried out in 96-well plates in the presence of 2.5μg of membrane protein, 0.5 mg of Ysi-poly-l-lysine SPA beads and 0.1 Uadenosine deaminase in a final volume of 200 μl of buffer A.Non-specific binding was defined using xanthine amine congener (XAC; 2μM). Compounds were tested at 10 concentrations from 10 μM-0.3 nM. Allassays were conducted in duplicate and repeated at least two times.Assay plates were incubated for 1 hour at room temperature beforecentrifugation and then bound ligand determined using a Packard Topcountscintillation counter. IC₅₀ values were calculated using a non-linearcurve fitting program and Ki values calculated using the Cheng-Prussoffequation.

[0178] The pKi value of compounds of the present application are in therange of 7.3 to 8.5, as described in the table below. Example No. hA₂(pKi) Example No. hA₂ (pKi) 1 7.7 8 8.0 2 7.8 9 7.9 3 7.8 10 8.1 4 7.711 8.1 5 8.4 12 7.3 6 8.1 13 8.0 7 8.5

[0179] The compounds of formula I and the pharmaceutically acceptablesalts of the compounds of formula I can be used as medicaments, e.g. inthe form of pharmaceutical preparations. The pharmaceutical preparationscan be administered orally, e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatine capsules, solutions, emulsions orsuspensions. The administration can, however, also be effected rectally,e.g. in the form of soppositories, parenterally, e.g. in the form ofinjection solutions.

[0180] The compounds of formula I can be processed with pharmaceuticallyinert, inorganic or organic carriers for the production ofpharmaceutical preparations. Lactose, corn starch or derivativesthereof, talc, stearic acids or its salts and the like can be used, forexample, as such carriers for tablets, coated tablets, dragées and hardgelatine capsules. Suitable carriers for soft gelatine capsules are, forexample, vegetable oils, waxes, fats, semi-solid and liquid polyols andthe like. Depending on the nature of the active substance no carriersare, however, usually required in the case of soft gelatine capsules.Suitable carriers for the production of solutions and syrups are, forexample, water, polyols, glycerol, vegetable oil and the like. Suitablecarriers for suppositories are, for example, natural or hardened oils,waxes, fats, semi-liquid or liquid polyols and the like.

[0181] The pharamaceutical preparations can, moreover, containpreservatives, solubilizers, stabilizers, wetting agents, emulsifiers,sweeteners, colorants, flavorants, salts for varying the osmoticpressure, buffers, masking agents or antioxidants. They can also containstill other therapeutically valuable substances.

[0182] Medicaments containing a compound of formula I or apharmaceutically acceptable salt thereof and a therapeutically inertcarrier are also an object of the present invention, as is a process fortheir production, which comprises bringing one or more compounds offormula I and/or pharmaceutically acceptable acid addition salts and, ifdesired, one or more other therapeutically valuable substances into agalenical administration form together with one or more therapeuticallyinert carriers.

[0183] In accordance with the invention compounds of formula I as wellas their pharmaceutically acceptable salts are useful in the control orprevention of illnesses based on the adenosine receptor antagonisticactivity, such as Alzheimer's disease, Parkinson's disease,neuroprotection, schizophrenia, anxiety, pain, respiration deficits,depression, asthma, allergic responses, hypoxia, ischaemia, seizure andsubstance abuse. Furthermore, compounds of the present invention may beuseful as sedatives, muscle relaxants, antipsychotics, antiepileptics,anticonvulsants and cardiaprotective agents and for the production ofcorresponding medicaments.

[0184] The most preferred indications in accordance with the presentinvention are those, which include disorders of the central nervoussystem, for example the treatment or prevention of certain depressivedisorders, neuroprotection and Parkinson's disease.

[0185] The dosage can vary within wide limits and will, of course, haveto be adjusted to the individual requirements in each particular case.In the case of oral administration the dosage for adults can vary fromabout 0.01 mg to about 1000 mg per day of a compound of general formulaI or of the corresponding amount of a pharmaceutically acceptable saltthereof. The daily dosage may be administered as single dose or individed doses and, in addition, the upper limit can also be exceededwhen this is found to be indicated. Tablet Formulation (Wet Granulation)mg/tablet Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound offormula I 5 25 100 500 2. Lactose Anhydrous DTG 125 105 30 150 3. Sta-Rx1500 6 6 6 30 4. Microcrystalline Cellulose 30 30 30 150 5. MagnesiumStearate 1 1 1 1 Total 167 167 167 831

[0186] Manufacturing Procedure

[0187] 1. Mix items 1, 2, 3 and 4 and granulate with purified water.

[0188] 2. Dry the granules at 50° C.

[0189] 3. Pass the granules through suitable milling equipment.

[0190] 4. Add item 5 and mix for three minutes; compress on a suitablepress. Capsule Formulation mg/capsule Item Ingredients 5 mg 25 mg 100 mg500 mg 1. Compound of formula I 5 25 100 500 2. Hydrous Lactose 159 123148 — 3. Corn Starch 25 35 40 70 4. Talc 10 15 10 25 5. MagnesiumStearate 1 2 2 5 Total 200 200 300 600

[0191] Manufacturing Procedure

[0192] 1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.

[0193] 2. Add items 4 and 5 and mix for 3 minutes.

[0194] 3. Fill into a suitable capsule.

[0195] The following preparation and examples illustrate the inventionbut are not intended to limit its scope.

EXAMPLE 13-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-1-(4-trifluoromethyl-cyclohexyl)-urea

[0196] 4-Methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine was firstreacted with phenyl chloroformate as described for(4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid benzyl ester inWO01/97786 and then with methyl-(4-trifluoromethyl-cyclohexyl)-amine.Usual workup, flash-chromatography (silica, eluentdichloromethane/methanol) and final evaporation of the solvent affordedthe title compound as white crystals (96% yield), mp 157-167° C. MS:m/e=473(M+H⁺). Following the general method of example 1 the compoundsof examples 2 to 12 were prepared.

EXAMPLE 2(trans)-3-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-1-(4-methyl-cyclohexyl)-urea

[0197] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine, phenylchloroformate and (trans)-methyl-(4-methyl-cyclohexyl)-amine, the titlecompound was prepared as off-white crystals (70% yield), mp 171-173° C.MS: m/e=420(M+H⁺).

EXAMPLE 3(trans)-1-(4-Hydroxymethyl-cyclohexyl)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea

[0198] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine, phenylchloroformate and (trans)-(4-hydroxymethyl-cyclohexyl)-methyl-amine, thetitle compound was prepared as light brown crystals (42% yield). MS:m/e=436(M+H⁺), mp 190° C. (dec).

EXAMPLE 4(trans)-1-(4-Methoxymethyl-cyclohexyl)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea

[0199] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine, phenylchloroformate and (trans)-(4-methoxymethyl-cyclohexyl)-methyl-amine, thetitle compound was prepared as white solid (73% yield), mp 141-143° C.MS: m/e=450(M+H⁺).

EXAMPLE 5(rac),(cis)-1-(3-Hydroxymethyl-cyclopentyl)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea

[0200] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine, phenylchloroformate and (rac)-(cis)-(3-methylamino-cyclopentyl)-methanol, thetitle compound was prepared as light yellow solid (58% yield), mp115-118° C. MS: m/e=421 (M+H⁺).

EXAMPLE 61-(endo)-(rac)-Bicyclo[2.2.1]hept-2-yl-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea

[0201] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine, phenylchloroformate and (endo)-(rac)-(bicyclo[2.2.1]hept-2-yl)-methyl-amine,the title compound was prepared as white solid (65% yield), mp 199-202°C. MS: m/e=417(M+H⁺).

EXAMPLE 7(exo)-(+)-3-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-1-(7-oxa-bicyclo[2.2.1]hept-2-yl)-urea

[0202] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine, phenylchloroformate and(−)-(exo)-methyl-(7-oxa-bicyclo[2.2.1]hept-2-yl)-amine, the titlecompound was prepared as light yellow crystals (82% yield), mp 202-204°C. MS: m/e=419(M+H⁺).

EXAMPLE 8(exo)-(−)-3-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-1-(7-oxa-bicyclo[2.2.1]hept-2-yl)-urea

[0203] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine, phenylchloroformate and(+)-(exo)-methyl-(7-oxa-bicyclo[2.2.1]hept-2-yl)-amine, the titlecompound was prepared as light yellow crystals (82% yield), mp 202-203°C. MS: m/e=419(M+H⁺).

EXAMPLE 9(rac)-(endo)-3-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-1-(7-oxa-bicyclo[2.2.1]hept-2-yl)-urea

[0204] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine, phenylchloroformate and(rac)-(endo)-methyl-(7-oxa-bicyclo[2.2.1]hept-2-yl)-amine, the titlecompound was prepared as white crystals (47% yield), mp 191-193° C. MS:m/e=419(M+H⁺).

EXAMPLE 10(rac)-1-(5-exo-Hydroxy-bicyclo[2.2.1]hept-2-exo-yl)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea

[0205] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine, phenylchloroformate and 5-(exo)-methylamino-bicyclo[2.2.1]heptan-2-(exo)-ol,the title compound was prepared as white crystals (10% yield), MS:m/e=433(M+H⁺), mp 189° C.

EXAMPLE 11(rac)-1-(5-exo-Hydroxy-bicyclo[2.2.1]hept-2-endo-yl)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea

[0206] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine, phenylchloroformate and 5-(endo)-methylamino-bicyclo[2.2.1]heptan-2-(exo)-ol,the title compound was prepared as white crystals (12% yield), MS:m/e=433(M+H⁺), mp 189° C.

EXAMPLE 121-Adamantan-1-yl-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea

[0207] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine, phenylchloroformate and adamantan-1-yl-methyl-amine, the title compound wasprepared as white crystals (76% yield), mp 165-176° C. MS:m/e=458(M+H⁺).

EXAMPLE 13 8-Oxa-3-aza-bicyclo[3.2.1]octane-3-carboxylic acid(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide

[0208] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine, phenylchloroformate and 8-oxa-3-aza-bicyclo[3.2.1]octane, the title compoundwas prepared as white crystals (67% yield), mp 229-231° C. MS:m/e=405(M+H⁺).

Intermediates EXAMPLE 14 Methyl-(4-trifluoromethyl-cyclohexyl)-amine

[0209]

[0210] The title compound was prepared from4-trifluoromethyl-cyclohexylamine (DE 2630562) by introduction of aethoxycarbonyl-group under standard conditions (ethylchloroformate/diisopropyl-ethalamine), and final reduction with lithiumaluminium hydride in tetrahydrofurane under standard conditions to givethe title compound as a light yellow oil, MS: m/e=168(M+H⁺). The titlecompound was crystallized as its hydrochloride by use of ethanolichydrogen chloride. White crystals, mp 202-204° C.

EXAMPLE 15 1-Methyl-4-(ds)-methylamino-cyclohexanol

[0211]

[0212] The title compound was prepared from(cis)-4-amino-1-methyl-cyclohexanol (WO9607657) in the same manner asdescribed for methyl-(4-trifluoromethyl-cyclohexyl)-amine. Whitecrystals, mp 123-124° C., MS: m/e=144(M+H⁺).

EXAMPLE 16 (−)-(exo)-Methyl-(7-oxa-bicyclo[2.2.1]hept-2-yl)-aminehydrochloride

[0213]

[0214] The title compound was prepared from(rac)-(exo)-methyl-(7-oxa-bicyclo[2.2.1]hept-2-yl)-amine (J. Med. Chem.1971, 14, 698) by benzylation under standard conditions (benzylbromide/diisopropyl-ethalamine), chiral resolution by preparative chiralHPLC (Chrialpak AD, eluent 2% isopropanol in heptane) and finaldeprotection under standard conditions (chloroethylchloroformate/methanol) to give the title compound as white solid.[α]_(D)=−6.2(c=0.23, dichloromethane).

[0215] The anantiomer(+)-(exo)-methyl-(7-oxa-bicyclo[2.2.1]hept-2-yl)-amine hydrochloride wasobtained from the earlier eluting fractions of the same resolution.

1. A compound of formula I

wherein R¹ is selected from the group consisting of cyclopentyl,cyclopentyl substituted by CF₃, cyclopentyl substituted by lower alkyl,cyclopentyl substituted by —(CH₂)_(n)OH, cyclopentyl substituted by—(CH₂)_(n)-O-lower alkyl, cyclohexyl, cyclohexyl substituted by CF₃,cyclohexyl substituted by lower alkyl, cyclohexyl substituted by—(CH₂)_(n)OH, cyclohexyl substituted by —(CH₂)_(n)-O-lower alkyl,1-bicyclo[2.2.1]hept-2-yl, 1-(7-oxa-bicyclo[2.2.1]hept-2-yl,1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-exo-yl,1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-endo-yl, and 1-adamantan-1-yl; andR² is lower alkyl; or R¹ and R² form together with the N-atom the group8-oxa-3-aza-bicyclo[3.2.1]octane; and n is 0 or 1; or a pharmaceuticallyacceptable salt thereof:
 2. A compound of formula I

wherein R¹ is selected from the group consisting of cyclopentyl,cyclopentyl substituted by CF₃, cyclopentyl substituted by lower alkyl,cyclopentyl substituted by —(CH₂)_(n)OH, cyclopentyl substituted by—(CH₂)_(n)-O-lower alkyl, cyclohexyl, cyclohexyl substituted by CF₃,cyclohexyl substituted by lower alkyl, cyclohexyl substituted by—(CH₂)_(n)OH, cyclohexyl substituted by —(CH₂)_(n)-O-lower alkyl,1-bicyclo[2.2.1]hept-2-yl, 1-(7-oxa-bicyclo[2.2.1]hept-2-yl,1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-exo-yl,1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-endo-yl, and 1-adamantan-1-yl; andR² is lower alkyl; and n is 0 or 1; or a pharmaceutically acceptablesalt thereof.
 3. A compound of formula I

wherein, R¹ and R² form together with the N-atom the group8-oxa-3-aza-bicyclo[3.2.1]octane; or a pharmaceutically acceptable saltthereof.
 4. The compound of formula I in accordance with claim 1,wherein R¹ is selected from the group consisting of cyclopentyl,cyclopentyl substituted by CF₃, cyclopentyl substituted by lower alkyl,cyclopentyl substituted by —(CH₂)_(n)OH, cyclopentyl substituted by—(CH₂)_(n)-O-lower alkyl, cyclohexyl, cyclohexyl substituted by CF₃,cyclohexyl substituted by lower alkyl, cyclohexyl substituted by—(CH₂)_(n)OH, and cyclohexyl substituted by —(CH₂)_(n)-O-lower alkyl. 5.The compound of formula I in accordance with claim 4, selected from thegroup consisting of3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-1-(4-trifluoromethyl-cyclohexyl)-urea,(trans)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-1-(4-methyl-cyclohexyl)-urea,(trans)-1-(4-hydroxymethyl-cyclohexyl)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea,(trans)-1-(4-methoxymethyl-cyclohexyl)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea,and (rac),(cis)-1-(3-hydroxymethyl-cyclopentyl)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea.6. The compound of formula I in accordance with claim 1, wherein R¹ isselected from the group consisting of 1-bicyclo[2.2.1]hept-2-yl,1-(7-oxa-bicyclo[2.2.1]hept-2-yl,1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-exo-yl, and1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-endo-yl or 1-adamantan-1-yl. 7.The compound of formula I in accordance with claim 6, selected from thegroup consisting of1-(endo)-(rac)-bicyclo[2.2.1]hept-2-yl-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea,(exo)-(+)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-1-(7-oxa-bicyclo[2.2.1]hept-2-yl)-urea,(exo)-(−)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-1-(7-oxa-bicyclo[2.2.1]hept-2-yl)-urea,(rac)-(endo)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-1-(7-oxa-bicyclo[2.2.1]hept-2-yl)-urea,(rac)-1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-exo-yl)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea,(rac)-1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-endo-yl)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea,and1-adamantan-1-yl-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea.8. The compound of formula I in accordance with claim 1, wherein R¹ andR² form together with the N-atom the group8-oxa-3-aza-bicyclo[3.2.1]octane.
 9. The compound of formula I inaccordance with claim 8, wherein the compound is8-oxa-3-aza-bicyclo[3.2.1]octane-3-carboxylic acid(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide.
 10. A process forpreparing a compound of formula I as defined in claim 1, which processcomprises reacting a compound of formula

with a compound of formula

to produce a compound of formula

wherein R¹ is selected from the group consisting of cyclopentyl,cyclopentyl substituted by CF₃, cyclopentyl substituted by lower alkyl,cyclopentyl substituted by —(CH₂)_(n)OH, cyclopentyl substituted by—(CH₂)_(n)-O-lower alkyl, cyclohexyl, cyclohexyl substituted by CF₃,cyclohexyl substituted by lower alkyl, cyclohexyl substituted by—(CH₂)_(n)OH, cyclohexyl substituted by —(CH₂)_(n)-O-lower alkyl,1-bicyclo[2.2.1]hept-2-yl, 1-(7-oxa-bicyclo[2.2.1]hept-2-yl,1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-exo-yl,1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-endo-yl, and 1-adamantan-1-yl; andR² is lower alkyl; or R¹ and R² form together with the N-atom the group8-oxa-3-aza-bicyclo[3.2.1]octane; and n is 0 or
 1. 11. A process forpreparing a compound of formula I as defined in claim 1, which processcomprises reacting a compound of formula

with a compound of formula

to produce a compound of formula

wherein R¹ is selected from the group consisting of cyclopentyl,cyclopentyl substituted by CF₃, cyclopentyl substituted by lower alkyl,cyclopentyl substituted by —(CH₂)_(n)OH, cyclopentyl substituted by—(CH₂)_(n)-O-lower alkyl, cyclohexyl, cyclohexyl substituted by CF₃,cyclohexyl substituted by lower alkyl, cyclohexyl substituted by—(CH₂)_(n)OH, cyclohexyl substituted by —(CH₂)_(n)-O-lower alkyl,1-bicyclo[2.2.1]hept-2-yl, 1-(7-oxa-bicyclo[2.2.1]hept-2-yl,1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-exo-yl,1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-endo-yl, and 1-adamantan-1-yl; andR² is lower alkyl; or R¹ and R² form together with the N-atom the group8-oxa-3-aza-bicyclo[3.2.1]octane; and n is 0 or 1; L is a leaving groupselected from the group consisting of such as halogen, —O-phenyl andO-lower alkyl.
 12. The process of claim 10 that further comprisesconverting the compounds obtained into a pharmaceutically acceptablesalt thereof.
 13. The process of claim 11 that further comprisesconverting the compounds obtained into a pharmaceutically acceptablesalt thereof.
 14. A pharmaceutical composition which comprises acompound of formula I

wherein R¹ is selected from the group consisting of cyclopentyl,cyclopentyl substituted by CF₃, cyclopentyl substituted by lower alkyl,cyclopentyl substituted by —(CH₂)_(n)OH, cyclopentyl substituted by—(CH₂)_(n)-O-lower alkyl, cyclohexyl, cyclohexyl substituted by CF₃,cyclohexyl substituted by lower alkyl, cyclohexyl substituted by—(CH₂)_(n)OH, cyclohexyl substituted by —(CH₂)_(n)-O-lower alkyl,1-bicyclo[2.2.1]hept-2-yl, 1-(7-oxa-bicyclo[2.2.1]hept-2-yl,1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-exo-yl,1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-endo-yl, and 1-adamantan-1-yl; andR² is lower alkyl; or R¹ and R² form together with the N-atom the group8-oxa-3-aza-bicyclo[3.2.1]octane; and n is 0 or 1; or a pharmaceuticallyacceptable salt thereof; and a pharmaceutically acceptable carrier. 15.A method of treating a disease based on adenosine A_(2A)-receptoractivity comprising administering to a patient in need thereof atherapeutically effective amount of at least one compound of formula I

wherein R¹ is selected from the group consisting of cyclopentyl,cyclopentyl substituted by CF₃, cyclopentyl substituted by lower alkyl,cyclopentyl substituted by —(CH₂)_(n)OH, cyclopentyl substituted by—(CH₂)_(n)-O-lower alkyl, cyclohexyl, cyclohexyl substituted by CP₃,cyclohexyl substituted by lower alkyl, cyclohexyl substituted by—(CH₂)_(n)OH, cyclohexyl substituted by —(CH₂)_(n)-O-lower alkyl,1-bicyclo[2.2.1]hept-2-yl, 1-(7-oxa-bicyclo[2.2.1]hept-2-yl,1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-exo-yl,1-(5-exo-hydroxy-bicyclo[2.2.1]hept-2-endo-yl, and 1-adamantan-1-yl; andR² is lower alkyl; or R¹ and R² form together with the N-atom the group8-oxa-3-aza-bicyclo[3.2.1]octane; and n is 0 or 1; or a pharmaceuticallyacceptable salt thereof.
 16. The method of claim 15 wherein the diseaseis selected from Alzheimer's disease, depression, Parkinson's diseaseand ADHD.